title: Role of autophagy in the resistance to tumour necrosis factor-related apoptosis-inducing ligand-induced apoptosis in papillary and anaplastic thyroid cancer cells.
abstract: Current alternative therapies for refractory thyroid cancer such as kinase inhibitors have limitations including incomplete response and toxicity. Although tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce cancer cell-specific apoptosis, various degrees of TRAIL resistance have been reported for different types of thyroid cancer cells. Here, we investigated if modulation of autophagy could improve sensitivity to TRAIL in papillary and anaplastic thyroid cancer cells. Human papillary thyroid cancer cells (TPC-1 cells) and human anaplastic thyroid cancer cells (FRO cells) were treated with TRAIL after transfection with ATG7 siRNA or control siRNA. Levels of autophagy and apoptosis were confirmed by Western blot of ATG7, LC3, caspase-3 and poly (ADP-ribose) polymerase. Viability index was determined by dimethyl-thiazole-diphenyltetrazolium bromide assay. Fraction of apoptotic cells was determined by flow cytometry. In TPC-1 cells, treatment with TRAIL increased the levels of autophagy. A low concentration (20 ng/ml) of TRAIL resulted in significantly decreased viability index and increased apoptosis. However, inhibition of autophagy with ATG7 siRNA desensitised the cells to TRAIL-induced apoptosis. In FRO cells, TRAIL did not increase the levels of autophagy. In contrast to TPC-1 cells, inhibition of autophagy with ATG7 siRNA sensitised FRO cells to TRAIL-induced apoptosis. Autophagy might contribute to the known sensitivity of papillary thyroid cancer cells to TRAIL-induced apoptosis. Inhibition of autophagy in anaplastic thyroid cancer cells could sensitise these cells to TRAIL-induced apoptosis.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-dong, Gangnam-gu, Seoul, 135-710, Republic of Korea.
authors.forename: Sang-Man
authors.initials: SM
authors.lastname: Jin
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Jang
authors.forename: Seo Young
authors.initials: SY
authors.lastname: Sohn
authors.forename: Na Kyung
authors.initials: NK
authors.lastname: Kim
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Joung
authors.forename: Yoon Young
authors.initials: YY
authors.lastname: Cho
authors.forename: Sun Wook
authors.initials: SW
authors.lastname: Kim
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Chung
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D002277:Carcinoma / Q000473:pathology*; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D000077273:Thyroid Cancer, Papillary; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000473:pathology*; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes